According to the world health organization (WHO) an estimated 2 billion people worldwide are infected with the hepatitis B Virus (HBV). More than 350 million patients live with chronic infection that results in 600,000 deaths worldwide every year.1 Currently, there are several nucleos(t)ide analogues such as lamivudine, adefovir, telbivudine, entecavir, clevudine, and tenofovir have been demonstrated their clinical efficacy.2,3 
Currently, entecavir and tenofovir are being prescribed as major anti-HBV agents for drug naïve as well as for the patients harboring adefovir and lamivudine resistant strains. However, the continuous use of entecavir also develops mutation, and particularly, in conjunction with lamivudine resistant mutation, entecavir becomes clinically ineffective.4 Therefore, viral mutations limit the use of currently approved drugs as the anti-HBV therapy.5 Thus, it is of great interest to discover anti-HBV agents, which are effective against drug-resistant HBV mutants
As parts of our continued efforts to identify new and effective agents for HBV therapy, we discovered 2′-β-fluoro-6′-methylene carbocyclic adenosine (FMCA, 1)6 and its phosphoramidate prodrug (FMCAP, 2)7 (FIG. 1) as promising agents. FMCA and FMCAP demonstrated the anti-HBV efficacy in both wild type as well as resistant mutants. FMCA (EC50 0.67) and FMCAP (EC50 0.054) maintain their anti-HBV potency in vitro against the entecavir resistant triple mutant (L180M+M204V+S202G) while entecavir losses 150 fold less effective against the mutant in comparison to wild type.8 To support ongoing biological and preclinical development, an efficient scale-up synthesis of FMCA was required.
Previously, we reported the synthesis of FMCA by a scheme which was long and tedious with an inefficient methodology from ribose for an initial discovery.6 Although our group has been extensively involved in the synthesis of carbocyclic nucleosides from D-ribose,9,10 this known procedure proves hazardous for a large scale preparation as an excess of MeI is required;11 further, it has a low overall yield.6 